Antioxidative therapy in an ex vivo human cartilage trauma-model: attenuation of trauma-induced cell loss and ECM-destructive enzymes by N-acetyl cysteine

Abstract

Objective: Mechanical trauma of articular cartilage results in cell loss and cytokine-driven inflammatory response. Subsequent accumulation of reactive oxygen (ROS) and nitrogen (RNS) species enhances the enzymatic degradation of the extracellular matrix (ECM). This study aims on the therapeutic potential of N-acetyl cysteine (NAC) in a human ex vivo cartilage trauma-model, focusing on cell- and chondroprotective features.

Design: Human full-thickness cartilage explants were subjected to a defined impact trauma (0.59 J) and treated with NAC. Efficiency of NAC administration was evaluated by following outcome parameters: cell viability, apoptosis rate, anabolic/catabolic gene expression, secretion and activity of matrix metalloproteinases (MMPs) and proteoglycan (PG) release.

Results: Continuous NAC administration increased cell viability and reduced the apoptosis rate after trauma. It also suppressed trauma-induced gene expression of ECM-destructive enzymes, such as ADAMTS-4, MMP-1, -2, -3 and -13 in a dosage- and time-depending manner. Subsequent suppression of MMP-2 and MMP-13 secretion reflected these findings on protein level. Moreover, NAC inhibited proteolytic activity of MMPs and reduced PG release.

Conclusion: In the context of this ex vivo study, we showed not only remarkable cell- and chondroprotective features, but also revealed new encouraging findings concerning the therapeutically effective concentration and treatment-time regimen of NAC. Its defense against chondrocyte apoptosis and catabolic enzyme secretion recommends NAC as a multifunctional add-on reagent for pharmaceutical intervention after cartilage injury. Taken together, our data increase the knowledge on the therapeutic potential of NAC after cartilage trauma and presents a basis for future in vivo studies.

Keywords: Cell protection; Chondroprotection; ECM degradation; Mechanical loading; N-acetyl cysteine; Posttraumatic osteoarthritis.